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Showing PPP1R15A — GADD34 is a alias.

PPP1R15A

Protein phosphatase 1 regulatory subunit 15A · UniProt O75807

Length
674 aa
Mass
73.5 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R15A (GADD34) is a stress-inducible regulatory subunit that converts the general protein phosphatase PP1 into a substrate-specific eIF2α phosphatase, providing the principal negative-feedback arm that terminates the integrated stress response (PMID:11381086, PMID:12824288). It functions as a scaffold: an N-terminal region bearing an amphipathic helix targets the holoenzyme to the ER membrane (and, via polar-face residues, to mitochondria), while a C-terminal bipartite PP1-docking module (KVRF plus RARA motifs) and a structurally independent eIF2α-binding motif together confer substrate selectivity, with both binding sites required for catalysis (PMID:11564868, PMID:12556489, PMID:21518769, PMID:26095357, PMID:26100893). Structural and reconstitution work established that GADD34-bound PP1 retains eIF2α activity while being restrained against generic substrates, and that the assembled holophosphatase is the target of conformation-altering small molecules such as Guanabenz and Sephin1 (PMID:26095357, PMID:28759048). Loss of GADD34 prolongs eIF2α phosphorylation and delays recovery of translation after ER stress, and is physiologically required for globin translation in erythroid precursors, antiviral type I IFN/IL-6 production, and starvation- and TFEB-driven autophagy and lysosomal biogenesis (PMID:12824288, PMID:16478986, PMID:22615568, PMID:32978159). Beyond eIF2α, GADD34 directs PP1 to additional substrates and pathways—dephosphorylating TβRI (via the Smad7 adaptor), TAK1 at Ser412 to dampen TLR/NF-κB signaling, and TSC2 to suppress mTOR and promote autophagy (PMID:14718519, PMID:24534530, PMID:17273797, PMID:21439266)—and also acts in eIF2α-independent roles, scaffolding CK1ε for TDP-43 Ser409/410 phosphorylation under oxidative stress, promoting SIRT1 dephosphorylation, and supporting Golgi trafficking of SNAT2 (PMID:29109149, PMID:28984870, PMID:29212034). GADD34 abundance is set at multiple levels: a uORF-containing 5′-UTR licenses preferential translation during eIF2α phosphorylation, an N-terminal degron and ER association drive proteasomal turnover, Tyr262 phosphorylation (reversed by TC-PTP) accelerates degradation, and a 3′-UTR AU-rich element subjects the mRNA to ZFP36-dependent decay (PMID:19131336, PMID:21518769, PMID:24092754, PMID:38602876); basal translation is repressed by these uORFs (PMID:19131336).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established the founding mechanism: GADD34 partners with PP1c to selectively dephosphorylate eIF2α and close the negative-feedback loop on the unfolded protein response.

    Evidence In vitro phosphatase assay, Co-IP, PP1-binding mutants, and CHOP reporter; plus yeast two-hybrid and truncation mapping of a PP1/inhibitor-1 complex

    PMID:11381086 PMID:11564868

    Open questions at the time
    • Did not resolve where in the cell the complex assembles
    • Structural basis of substrate restriction not defined
  2. 2003 High

    Defined the spatial and modular architecture—N-terminal ER targeting plus a C-terminal bipartite PP1-binding domain—and showed ER localization is necessary for cellular eIF2α dephosphorylation.

    Evidence GFP-GADD34 live imaging, deletion analysis, and thapsigargin/tunicamycin eIF2α reversal assay; KO MEFs showing prolonged p-eIF2α and delayed translational recovery

    PMID:12556489 PMID:12824288

    Open questions at the time
    • Why PP1 binding alone is insufficient remained unexplained
    • Membrane-association determinants not yet mapped at residue level
  3. 2004 High

    Showed GADD34-PP1 substrate range extends beyond eIF2α via adaptors, dephosphorylating the TGFβ type I receptor through Smad7.

    Evidence Co-IP, Smad7 RNAi, and in vitro dephosphorylation with TGFβ signaling readouts

    PMID:14718519

    Open questions at the time
    • Stoichiometry of the Smad7/GADD34/PP1/TβRI complex unresolved
    • Whether ER-targeting is involved here not addressed
  4. 2006 High

    Demonstrated a physiological requirement for the eIF2α phosphatase activity in erythroid translation, linking ISR feedback to hemoglobin synthesis.

    Evidence Gadd34-null mice, reticulocyte biochemistry, eIF2α phosphorylation assays

    PMID:16478986

    Open questions at the time
    • Cell-autonomy versus systemic effects not dissected
    • Relationship to other eIF2α phosphatases (CReP) unaddressed
  5. 2009 High

    Explained how GADD34 is preferentially translated precisely when eIF2α is phosphorylated, via 5′-UTR uORFs that repress basal but enable stress-induced translation; a competitive peptide showed PP1/GADD34 dissociation alone drives calreticulin surface exposure.

    Evidence Polysome profiling, 5′-UTR/uORF reporter mutations; cell-penetrating GADD34 peptide with CRT surface staining

    PMID:19131336 PMID:19901557

    Open questions at the time
    • uORF mechanism and CRT-exposure work are independent and not mechanistically linked
    • In vivo relevance of CRT exposure not established
  6. 2008 High

    Resolved how GADD34 is rapidly turned over, identifying an N-terminal degron and ER-association-promoted proteasomal degradation that limit feedback strength.

    Evidence Pulse-chase stability assays, deletion mutants, proteasome inhibitors, polyubiquitination detection

    PMID:18794359

    Open questions at the time
    • Identity of the responsible E3 ligase not determined
    • Coupling between ER association and ubiquitination machinery unknown
  7. 2011 High

    Pinpointed the amphipathic-helix residues governing ER versus mitochondrial targeting and tied membrane association to turnover, while showing cytosolic GADD34 retains catalytic scaffolding.

    Evidence FRAP, fluorescence protease protection, cysteine-substitution modification, proteasome inhibitor assays; plus TSC2-Thr1462 dephosphorylation in starvation-induced autophagy in KO mice

    PMID:21439266 PMID:21518769

    Open questions at the time
    • Functional purpose of mitochondrial targeting not defined
    • How GADD34 selects TSC2 versus eIF2α not resolved
  8. 2012 High

    Connected GADD34 to innate antiviral immunity, showing PKR-dependent GADD34 induction is required for type I IFN/IL-6 and host defense against Chikungunya virus.

    Evidence KO MEFs, dsRNA stimulation, cytokine ELISA, in vivo viral challenge

    PMID:22615568

    Open questions at the time
    • Whether cytokine effect is via eIF2α dephosphorylation or translation reprogramming not isolated
    • Substrate(s) in the IFN pathway unidentified
  9. 2013 Medium

    Expanded GADD34 into mTOR/Akt and stress-injury signaling: it sequesters TRAF6 from Akt after brain injury, and is inhibited by HTLV-1 HBZ to activate mTOR and suppress autophagy.

    Evidence Co-IP, ChIP, controlled cortical impact model with lentiviral knockdown; and HBZ NES/Co-IP analysis with S6K and autophagy readouts

    PMID:23708656 PMID:23907468

    Open questions at the time
    • TRAF6 mechanism is phosphatase-independent and from a single lab
    • Direct versus indirect effects on mTOR not fully separated
  10. 2014 Medium

    Identified TAK1 Ser412 as a GADD34-PP1 substrate, defining a phosphatase-based brake on TLR/NF-κB inflammatory signaling.

    Evidence Reciprocal Co-IP, GADD34 siRNA, TAK1 S412A mutant, in vivo LPS endotoxin shock

    PMID:24534530

    Open questions at the time
    • Single-lab finding without structural confirmation of TAK1 docking
    • How GADD34 is recruited to TAK1 not mapped
  11. 2015 High

    Provided the structural and biochemical basis of substrate specificity—independent PP1- and eIF2α-binding sites—and identified a discrete, virally conserved eIF2α-binding motif, while showing Tyr262 phosphorylation (reversed by TC-PTP) controls turnover.

    Evidence NMR/crystallography with in vitro reconstitution and mutagenesis; point mutagenesis of the eIF2α motif with yeast PKR assay; mass spectrometry and TC-PTP substrate-trapping/KO

    PMID:24092754 PMID:26095357 PMID:26100893

    Open questions at the time
    • Full holoenzyme-substrate ternary structure not solved
    • Kinase generating pTyr262 not identified
  12. 2016 Medium

    Showed GADD34 shapes the translatome in both unstressed (secretome) and stressed states, and revealed AKT/PERK and CReP compensation when GADD34 is lost.

    Evidence KO cells with ribosome profiling, AKT inhibitor, CReP monitoring

    PMID:27161320

    Open questions at the time
    • Direct targets among secretome mRNAs not defined
    • Mechanism of CReP/AKT compensation incompletely mapped
  13. 2017 High

    Reconstitution and pharmacology defined how Guanabenz/Sephin1 act on the holophosphatase and uncovered eIF2α-independent GADD34 functions in SIRT1 dephosphorylation, TDP-43 kinase scaffolding, and Golgi/SNAT2 trafficking; the drug mechanism remained contested.

    Evidence Recombinant R15A/R15B holophosphatase reconstitution with limited proteolysis (positive) versus in vitro reconstitution plus KO and eIF2α-S51A knock-in (negative); Co-IP/KO studies for SIRT1, CK1ε/TDP-43, and SNAT2 trafficking

    PMID:28447936 PMID:28759048 PMID:28984870 PMID:29109149 PMID:29212034

    Open questions at the time
    • Whether Guanabenz/Sephin1 act through PPP1R15A is directly contradicted between studies
    • The eIF2α-independent functions are each single-lab and lack structural detail
  14. 2020 High

    Placed GADD34 at the convergence of mTORC1 and ISR pathways, as a direct TFEB target whose eIF2α dephosphorylation enables autophagic flux and lysosomal biogenesis during starvation.

    Evidence KO cells, TFEB ChIP, eIF2α phosphorylation assays, autophagy flux and lysosome biogenesis readouts

    PMID:32978159

    Open questions at the time
    • How translational relief is selectively channeled to autophagy transcripts not resolved
  15. 2024 Medium

    Completed the regulatory picture by adding a 3′-UTR ARE/ZFP36 mRNA-decay layer and a BDNF-driven, cofilin/G-actin-dependent neuronal translation role that sets ISR thresholds and synaptic plasticity.

    Evidence ARE reporter and ZFP36 binding with mRNA stability assays; primary neuron BDNF stimulation with KO/KD, cofilin inhibition, polysome profiling

    PMID:38219147 PMID:38602876

    Open questions at the time
    • Mechanism by which G-actin enables eIF2α dephosphorylation is novel and single-lab
    • Integration of ARE control with uORF translational control not jointly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single scaffold dynamically partitions PP1 among its many substrates (eIF2α, TSC2, TAK1, TβRI, SIRT1) in time and space, and whether the contested small-molecule mechanism reflects holoenzyme conformation or off-target effects.
  • No structure of GADD34-PP1 bound to non-eIF2α substrates
  • Direct contradiction over Guanabenz/Sephin1 mechanism unresolved
  • Recruitment determinants for adaptor-mediated substrates not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CSNK1EEIF2S1MAP3K7PPP1CAPTPN2SIRT1SMAD7TSC2
Complex memberships
GADD34-PP1 holophosphataseGADD34/CK1ε/TDP-43 kinase scaffoldGADD34/PP1/hSNF5(INI1)GADD34/PP1/inhibitor-1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 GADD34 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promotes the dephosphorylation of eIF2α in vitro; mutations interfering with PP1c interaction prevent eIF2α dephosphorylation and block attenuation of CHOP. GADD34 thus acts as a negative feedback regulator of the unfolded protein response. In vitro phosphatase assay, co-immunoprecipitation, retroviral overexpression with PP1-binding mutants, CHOP::GFP reporter screen The Journal of cell biology High 11381086
2001 GADD34 assembles a novel signaling complex containing PP1 and inhibitor-1 (I-1). I-1 binds the central domain of GADD34 (aa 180–483), PP1 binds near the C-terminus (aa 483–619). GADD34-bound PP1 retains eIF2α phosphatase activity while GADD34 inhibits PP1-catalyzed dephosphorylation of phosphorylase a, indicating substrate selectivity conferred by GADD34. Yeast two-hybrid, recombinant protein pulldown, affinity isolation, brain extract analysis (hibernating vs. active ground squirrel) Molecular and cellular biology High 11564868
2003 GADD34 targets PP1α to the endoplasmic reticulum via its N-terminal 180 residues containing an amphipathic/ER-targeting sequence; the C-terminal bipartite domain (canonical KVRF PP1-binding motif plus novel RARA sequence) is required for PP1 binding. ER localization is necessary but PP1 binding alone is insufficient for eIF2α dephosphorylation in cells. GFP-GADD34 live-cell imaging, N-terminal and C-terminal deletion analysis, thapsigargin/tunicamycin eIF2α phosphorylation reversal assay Molecular and cellular biology High 12556489
2003 GADD34 knockout MEFs show prolonged eIF2α phosphorylation and delayed recovery from protein synthesis shutoff after thapsigargin or DTT treatment, establishing GADD34 as an in vivo eIF2α phosphatase regulator required for recovery from ER stress. GADD34 knockout mouse-derived MEFs, Western blot for p-eIF2α, protein synthesis recovery assay FASEB journal High 12824288
2004 Smad7 acts as an adaptor that recruits the GADD34–PP1c complex to the TGFβ type I receptor (TβRI), leading to dephosphorylation of TβRI and negative feedback on TGFβ signaling. SARA enhances PP1c recruitment to the Smad7–GADD34 complex by controlling PP1c subcellular localization. Co-immunoprecipitation, RNA interference knockdown of Smad7, in vitro dephosphorylation assay, TGFβ signaling readouts The Journal of cell biology High 14718519
2006 Gadd34-null mice display decreased hemoglobin content and reduced initiation of globin translation in reticulocytes, establishing that GADD34/PP1c-mediated eIF2α dephosphorylation is required for normal hemoglobin synthesis in erythroid precursors. Gadd34-null mouse analysis, reticulocyte biochemistry, eIF2α phosphorylation assays Molecular and cellular biology High 16478986
2007 GADD34 forms a stable complex with TSC1/2 and causes dephosphorylation of TSC2, thereby inhibiting mTOR signaling and protecting cells from apoptosis under bioenergetic stress. Co-immunoprecipitation, Western blot for TSC2 phosphorylation, cell viability assays International journal of molecular medicine Medium 17273797
2008 GADD34 is polyubiquitinated and degraded by the 26S proteasome via an N-terminal degron; deletion of N-terminal sequences or addition of N-terminal epitopes stabilizes the protein. Internal PEST repeats modulate PP1 binding and activity without affecting stability. ER association promotes proteasomal degradation of GADD34. Pulse-chase stability assays, N-terminal/internal deletion mutants, proteasome inhibitors, polyubiquitination detection, CFTR aggregation assay Molecular and cellular biology High 18794359
2009 The 5′-UTR of GADD34 mRNA contains upstream open reading frames (uORFs) that repress basal translation but direct efficient translation during eIF2α phosphorylation; the downstream uORF is the key regulatory element mediating stress-induced translational upregulation. Polysome profiling, 5′-UTR reporter constructs, uORF mutation analysis The Journal of biological chemistry High 19131336
2011 ER association of GADD34 is mediated by an amphipathic helix (valine 25 and leucine 29 on hydrophobic face); mitochondrial association requires arginine residues on the polar surface of the same helix. ER-associated GADD34 has reduced mobility (FRAP), promotes proteasomal degradation, and alters ER morphology, whereas a cytosolic mutant (V25R) is more stable yet retains PP1α scaffolding and eIF2α dephosphorylation activity. GFP-GADD34 live imaging, FRAP, fluorescence protease protection, cysteine-substitution chemical modification, proteasome inhibitor assays The Journal of biological chemistry High 21518769
2011 GADD34 bound to TSC1/2 and dephosphorylated TSC2 at Thr1462 under starvation conditions, suppressing mTOR activity and thereby inducing autophagy in vivo and in vitro; this effect was absent in GADD34 KO mice. Co-immunoprecipitation, Western blot for TSC2/p-TSC2, autophagy markers (LC3), GADD34 KO mice Biochemical and biophysical research communications Medium 21439266
2012 GADD34 (Ppp1r15a) is required for type I IFN and IL-6 production in MEFs stimulated with dsRNA; GADD34 expression in this context is dependent on PKR activation, linking cytosolic dsRNA sensing to the ATF4 branch of the UPR and antiviral immunity. GADD34-deficient fibroblasts and neonatal mice are extremely susceptible to Chikungunya virus infection. GADD34 KO MEFs, dsRNA stimulation, IFN/IL-6 ELISA, Chikungunya viral infection survival assay PLoS pathogens High 22615568
2013 GADD34 upregulation following traumatic brain injury binds TRAF6 and prevents its interaction with Akt, retaining Akt in the cytosol and blocking phosphorylation at T308. ATF4 binds the GADD34 promoter to induce its expression after TBI. In vivo lentiviral GADD34 knockdown rescues Akt activation and attenuates TBI-induced neuronal death. Co-immunoprecipitation, ChIP, controlled cortical impact mouse model, lentiviral shRNA knockdown, Akt T308 phosphorylation Western blot Cell death & disease Medium 23907468
2013 HTLV-1 HBZ interacts with GADD34 via its N-terminal region (exported via CRM1-dependent NES) in the cytoplasm, inhibiting GADD34 activity and thereby activating mTOR signaling (increased S6K phosphorylation) and suppressing starvation-induced autophagy. Co-immunoprecipitation, NES mutant analysis, nuclear export inhibitor (leptomycin B), S6K phosphorylation Western blot, autophagy assay Oncogene Medium 23708656
2014 The PP1/GADD34 holoenzyme negatively regulates TLR signaling by dephosphorylating TAK1 at serine 412; GADD34 specifies PP1 to TAK1, and GADD34 depletion abolishes the TAK1–PP1 interaction, relieves PP1-mediated inhibition of TLRs, and enhances NF-κB/MAPK activation and proinflammatory cytokine production. Co-immunoprecipitation, GADD34 siRNA knockdown, TAK1 S412A mutant, LPS-induced endotoxin shock in vivo Journal of immunology Medium 24534530
2015 Crystal/NMR structural and functional analysis of the GADD34:PP1 holoenzyme reveals that GADD34 functions as a scaffold with independent binding sites for PP1 and eIF2α, both required for substrate-specific dephosphorylation. Structural analysis (NMR/crystallography), in vitro phosphatase reconstitution, mutagenesis of PP1- and eIF2α-binding sites Cell reports High 26095357
2015 A novel eIF2α-binding motif (consensus Rx[Gnl]x(1-2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc]) maps to the C-terminus of GADD34 at a site distinct from the PP1-binding motif; point mutations in this motif impair eIF2α interaction and dephosphorylation; this motif is conserved in viral orthologs (HSV ICP34.5, African swine fever virus, Canarypox virus). Co-immunoprecipitation, point mutagenesis, in vitro eIF2α dephosphorylation assay, yeast PKR toxicity suppression assay Proceedings of the National Academy of Sciences of the United States of America High 26100893
2015 GADD34 protein levels are controlled by phosphorylation at tyrosine 262, which enhances proteasomal turnover; TC-PTP (PTPN2) was identified as the GADD34 phosphatase acting on pTyr262 by substrate-trapping. Reduced GADD34 levels in TC-PTP-null MEFs sensitize cells to ER stress-induced apoptosis. Mass spectrometry, phosphomimetic and phospho-null mutants, substrate-trapping pulldown with TC-PTP, TC-PTP KO MEFs The Journal of biological chemistry Medium 24092754
2016 GADD34 drives changes in mRNA translation in unstressed cells targeting the secretome; following UPR activation GADD34 is essential for UPR translational program progression — in its absence, eIF2α phosphorylation is persistently enhanced and the UPR translational program is significantly attenuated. Compensation occurs via AKT-mediated PERK suppression and increased CReP expression. GADD34 KO cells, ribosome profiling/polysome analysis, AKT inhibitor, CReP expression monitoring Molecular and cellular biology Medium 27161320
2017 Guanabenz and Sephin1 do not affect PP1–PPP1R15A complex stability or substrate-specific eIF2α dephosphorylation in vitro, and eIF2α-P dephosphorylation proceeds normally in Sephin1-treated cells by kinase shut-off experiment. Sephin1 effects on IRE1/UPR are independent of Ppp1r15a deletion and eIF2α phosphorylation status. In vitro PP1–PPP1R15A reconstitution, kinase shut-off eIF2α-P dephosphorylation assay, Ppp1r15a KO cells, CRISPR eIF2α-S51A knock-in cells eLife High 28447936
2017 Reconstituted human recombinant R15A-PP1 and R15B-PP1 holophosphatases display substrate-specific eIF2α dephosphorylation activity; Guanabenz and Sephin1 induce a selective conformational change in R15A (detected by limited proteolysis resistance) that alters eIF2α recruitment, preventing its dephosphorylation. Recombinant holophosphatase reconstitution, limited proteolysis, in vitro eIF2α dephosphorylation assay Nature structural & molecular biology High 28759048
2017 Oxidative stress (arsenite) promotes SIRT1 recruitment to a cytoplasmic GADD34/PP1α complex; GADD34/PP1α mediates dephosphorylation of both eIF2α (pSer51) and SIRT1 (pSer47), and SIRT1 dephosphorylation increases its deacetylase activity. Loss of GADD34 results in persistent phosphorylation of both substrates and altered cell fate. Mass spectrometry (GADD34 acetylation), Co-IP of GADD34/PP1α/eIF2α/SIRT1 complex, GADD34 KO MEFs, in vitro SIRT1 deacetylase activity assay Cell death and differentiation Medium 28984870
2017 Under chronic oxidative stress (arsenite), GADD34 recruits TDP-43 and casein kinase-1ε (CK1ε) to form a kinase scaffold complex; CK1ε bound to GADD34 catalyzes TDP-43 phosphorylation at serines 409/410 — a modification linked to TDP-43 proteinopathies. This GADD34 kinase-scaffold function is distinct from its phosphatase-regulatory role. Co-immunoprecipitation, GADD34 KO MEFs, mass spectrometry, Western blot for TDP-43 pSer409/410 The Journal of biological chemistry Medium 29109149
2017 GADD34 promotes Golgi trafficking and plasma membrane localization of the amino acid transporter SNAT2 during hyperosmotic stress, independent of its ISR/eIF2α role. GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation, enabling cis-to-trans Golgi trafficking. GADD34 KO cells, live Golgi imaging, SNAT2 trafficking assay, PP1 activity measurements Cell reports Medium 29212034
2019 GADD34 protects hepatocellular carcinoma cells from TRAIL-induced apoptosis by stabilizing MCL-1 protein through a TRAF6/TAB1/ERK signaling axis that inhibits proteasomal degradation of MCL-1. GADD34 does not affect MCL-1 transcription but enhances its protein stability. GADD34 knockdown/overexpression, MCL-1 stability assays, proteasome inhibitor MG132, ERK phosphorylation Western blot, TRAIL apoptosis assay The Journal of biological chemistry Medium 30782845
2020 TFEB directly activates GADD34 expression during starvation; GADD34 in turn dephosphorylates eIF2α to relieve translational repression and enable lysosomal biogenesis and sustained autophagic flux. The TFEB–GADD34 axis integrates mTORC1 and ISR pathways to resolve the conflict between translational arrest and autophagy-driven transcriptional programs. GADD34 KO cells, TFEB ChIP, eIF2α phosphorylation assays, autophagy flux measurements, lysosome biogenesis assays Science advances High 32978159
2024 The 3′-UTR of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by ZFP36 family proteins, promoting rapid mRNA decay under normal conditions and mRNA stabilization during stress, thereby constituting a post-transcriptional layer of GADD34 regulation that sets threshold for ISR responsiveness. ARE reporter assays, ZFP36 family protein binding analysis, mRNA stability measurements, stress-response time course Cell reports Medium 38602876
2024 BDNF stimulation of primary neurons induces GADD34 translation, which facilitates eIF2α dephosphorylation to promote de novo protein synthesis. GADD34's ability to dephosphorylate eIF2α in this context requires G-actin generated by cofilin. GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Primary rodent neuron culture, BDNF stimulation, GADD34 KO/knockdown, cofilin inhibition, polysome profiling, de novo protein synthesis assay Cell reports Medium 38219147
2002 hSNF5/INI1 binds GADD34 in part through the PP1 docking site, does not compete with PP1 for GADD34 binding, and forms a stable heterotrimeric GADD34/PP1/hSNF5 complex; hSNF5/INI1 weakly stimulates PP1 activity both in solution and in complex with GADD34. Co-immunoprecipitation, in vitro pulldown, phosphatase activity assay The Journal of biological chemistry Medium 12016208
2003 BAG-1 interacts with GADD34 in vitro and in cells; Hsp70/Hsc70 and PP1 associate reversibly with the GADD34–BAG-1 complex and their dissociation is promoted by ATP; BAG-1 negatively modulates GADD34-bound PP1 activity and suppresses GADD34-mediated colony-formation inhibition. Yeast two-hybrid, in vitro pulldown, Co-IP in SW480 cells, PP1 phosphatase activity assay, colony formation assay Molecular and cellular biology Medium 12724406
2009 A GADD34-derived peptide that competitively disrupts the PP1/GADD34 complex stimulates eIF2α phosphorylation and triggers calreticulin (CRT) surface exposure without inducing apoptosis when introduced into cells, demonstrating that PP1/GADD34 dissociation is sufficient for CRT exposure. Anthracyclines also stimulate PP1/GADD34 complex dissociation. Molecular modeling, cell-penetrating GADD34 peptide, Co-IP disruption assay, CRT surface staining, apoptosis assay Cell cycle Medium 19901557

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. The Journal of cell biology 1173 11381086
2003 Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and cellular biology 318 12556489
2001 Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Molecular and cellular biology 228 11564868
2004 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. The Journal of cell biology 209 14718519
2009 An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. The Journal of biological chemistry 202 19131336
2003 The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 201 12824288
1997 Mammalian GADD34, an apoptosis- and DNA damage-inducible gene. The Journal of biological chemistry 155 9153226
1996 A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. The EMBO journal 136 8887567
1999 Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Molecular and cellular biology 132 10490642
2015 Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase. Cell reports 123 26095357
2001 Peroxynitrite induces GADD34, 45, and 153 VIA p38 MAPK in human neuroblastoma SH-SY5Y cells. Free radical biology & medicine 114 11163539
2015 Is there a causal relationship between genetic changes and radiomics-based image features? An in vivo preclinical experiment with doxycycline inducible GADD34 tumor cells. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 109 26163091
2012 Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection. PLoS pathogens 100 22615568
2009 Inhibition of protein kinase R activation and upregulation of GADD34 expression play a synergistic role in facilitating coronavirus replication by maintaining de novo protein synthesis in virus-infected cells. Journal of virology 89 19776135
1997 The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34. Journal of virology 86 9371605
2017 PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLife 81 28447936
1998 Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents. Oncogene 80 9811446
2017 Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors. Nature structural & molecular biology 74 28759048
2015 An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α. Proceedings of the National Academy of Sciences of the United States of America 74 26100893
2013 GADD34 induces cell death through inactivation of Akt following traumatic brain injury. Cell death & disease 69 23907468
1999 A herpesvirus ribosome-associated, RNA-binding protein confers a growth advantage upon mutants deficient in a GADD34-related function. Journal of virology 67 10074192
2012 Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 66 22315398
2017 Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA. The EMBO journal 60 28100675
2008 Control of cellular GADD34 levels by the 26S proteasome. Molecular and cellular biology 60 18794359
2004 Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 15059970
2020 GADD34 is a modulator of autophagy during starvation. Science advances 56 32978159
2001 Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors. International journal of cancer 56 11241327
2004 Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression. Journal of neurochemistry 55 14675157
2006 Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma. Cancer biology & therapy 54 16294031
2003 GADD34 induces p53 phosphorylation and p21/WAF1 transcription. Journal of cellular biochemistry 50 14635196
2018 Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 49 29511029
1999 Activation of MYD116 (gadd34) expression following transient forebrain ischemia of rat: implications for a role of disturbances of endoplasmic reticulum calcium homeostasis. Brain research. Molecular brain research 46 9878749
2008 Overexpression of GADD34 enhances production of recombinant human antithrombin III in Chinese hamster ovary cells. Journal of bioscience and bioengineering 44 19134553
2015 Quercetin reduces eIF2α phosphorylation by GADD34 induction. Neurobiology of aging 43 26070242
2014 Phosphatase holoenzyme PP1/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 42 24534530
2016 GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation. Cell death & disease 41 27171261
2007 GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. International journal of molecular medicine 40 17273797
2002 The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity. The Journal of biological chemistry 39 12016208
2013 HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm. Oncogene 38 23708656
2009 Disruption of the PP1/GADD34 complex induces calreticulin exposure. Cell cycle (Georgetown, Tex.) 38 19901557
2016 Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Molecular and cellular biology 37 27161320
2011 Gadd34 induces autophagy through the suppression of the mTOR pathway during starvation. Biochemical and biophysical research communications 37 21439266
2011 GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway. Experimental cell research 36 21925170
2003 Gadd34 functional domains involved in growth suppression and apoptosis. Oncogene 36 12813455
1999 Cloning of a GADD34-like gene that interacts with the zinc-finger transcription factor which binds to the p21(WAF) promoter. Biochemical and biophysical research communications 36 10066455
2017 Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function. Cell death and differentiation 35 28984870
2002 Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat. The European journal of neuroscience 35 12099899
2017 Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration. The Journal of biological chemistry 34 29109149
2003 Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions. Molecular and cellular biology 32 12724406
2015 Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34. Oxidative medicine and cellular longevity 31 25821552
2006 Gadd34 requirement for normal hemoglobin synthesis. Molecular and cellular biology 31 16478986
2010 Selenium decreases thyroid cancer cell growth by increasing expression of GADD153 and GADD34. Nutrition and cancer 30 20043261
2017 GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells. Cell reports 29 29212034
2007 Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway. Journal of virology 29 17670836
2011 Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein. The Journal of biological chemistry 28 21518769
2000 Interaction between DNA-damage protein GADD34 and a new member of the Hsp40 family of heat shock proteins that is induced by a DNA-damaging reagent. The Biochemical journal 28 11104688
2023 The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP). International journal of molecular sciences 26 38139150
2022 A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress. FEBS open bio 26 36097827
2014 Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury. PloS one 25 25386686
2019 The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells. The Journal of biological chemistry 23 30782845
2016 GADD34 Keeps the mTOR Pathway Inactivated in Endoplasmic Reticulum Stress Related Autophagy. PloS one 23 27992581
2015 GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy. Scientific reports 23 25659802
2015 Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model. Cancer immunology, immunotherapy : CII 23 25832002
2022 Translation Rescue by Targeting Ppp1r15a through Its Upstream Open Reading Frame in Sepsis-Induced Acute Kidney Injury in a Murine Model. Journal of the American Society of Nephrology : JASN 22 36283811
2016 Regulation of de novo translation of host cells by manipulation of PERK/PKR and GADD34-PP1 activity during Newcastle disease virus infection. The Journal of general virology 22 26869028
2015 GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance. Scientific reports 22 26316333
2010 N-terminally truncated GADD34 proteins are convenient translation enhancers in a human cell-derived in vitro protein synthesis system. Biotechnology letters 22 20349333
1999 Evidence for the interaction between Translin and GADD34 in mammalian cells. Biochimica et biophysica acta 22 10434033
2024 Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress. Cell reports 20 38602876
2019 Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS. Neurobiology of disease 20 31837419
2015 Increased GADD34 in oligodendrocytes in Alzheimer's disease. Neuroscience letters 20 26142647
2016 Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies. Autoimmunity 19 26829377
2015 Effects of growth arrest and DNA damage-inducible protein 34 (GADD34) on inflammation-induced colon cancer in mice. British journal of cancer 19 26196182
2000 Interaction between GADD34 and kinesin superfamily, KIF3A. Biochemical and biophysical research communications 19 10631107
2022 Salidroside attenuates sepsis-associated acute lung injury through PPP1R15A mediated endoplasmic reticulum stress inhibition. Bioorganic & medicinal chemistry 18 35985062
2018 Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex. Science signaling 18 29363586
2016 Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression. The Journal of biological chemistry 18 27129771
2004 GADD34 protein levels increase after transient ischemia in the cortex but not in the CA1 subfield: implications for post-ischemic recovery of protein synthesis in ischemia-resistant cells. Journal of neurochemistry 18 15255948
2024 PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma. JHEP reports : innovation in hepatology 17 38882672
2021 Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF. Scientific reports 17 34732748
2022 Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis. Cell death & disease 16 35501353
2017 Functional validation of ATF4 and GADD34 in Neuro2a cells by CRISPR/Cas9-mediated genome editing. Molecular and cellular biochemistry 15 28825160
2015 Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity. The Journal of biological chemistry 15 26041779
2014 Induction of GADD34 Regulates the Neurotoxicity of Amyloid β. American journal of Alzheimer's disease and other dementias 15 25204313
2018 Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of . The Journal of biological chemistry 14 29491143
2009 EBNA3C interacts with Gadd34 and counteracts the unfolded protein response. Virology journal 14 20040105
2025 Protein phosphatase 1 regulatory subunit 15 A (PPP1R15A) promoted the progression of gastric cancer by activating cell autophagy under energy stress. Journal of experimental & clinical cancer research : CR 13 39948597
2023 Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity. iScience 13 36718369
2021 Growth arrest and DNA damage-inducible protein 34 (GADD34) contributes to cerebral ischemic injury and can be detected in plasma exosomes. Neuroscience letters 13 34098025
2021 GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis. Veterinary research 13 34930429
2015 GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition. Anticancer research 13 26408692
2004 Up-regulation of a growth arrest and DNA damage protein (GADD34) in the ischaemic human brain: implications for protein synthesis regulation and DNA repair. Neuropathology and applied neurobiology 12 15541008
2019 Capsaicin Induces ATF4 Translation with Upregulation of CHOP, GADD34 and PUMA. Biological & pharmaceutical bulletin 11 31366879
2013 Phosphorylation at tyrosine 262 promotes GADD34 protein turnover. The Journal of biological chemistry 11 24092754
2021 Guanabenz Sensitizes Glioblastoma Cells to Sunitinib by Inhibiting GADD34-Mediated Autophagic Signaling. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 10 33410111
2016 Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer. Journal of cancer research and clinical oncology 10 27177629
2007 GADD34 induces p21 expression and cellular senescence. Oncology reports 10 17487408
2005 Evolution of GADD34 expression after focal cerebral ischaemia. Brain research 10 15713259
2024 The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation. Cell reports 9 38219147
2019 GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated translational inhibition. Virology 9 31778897

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